PROJECT SUMMARY De novo loss-of-function mutations in the voltage-gated sodium channel SCN1A (encoding Nav1.1) are the main cause of Dravet syndrome (DS), a catastrophic early-life encephalopathy associated with prolonged and recurrent febrile seizures (FSs), treatment-resistant afebrile epilepsy, cognitive and behavioral deficits, and a 15-20% mortality rate. SCN1A mutations also lead to genetic epilepsy with febrile seizures plus (GEFS+), an inherited disorder characterized by early-life FSs and the development of a wide range of adult epilepsy subtypes. Current anti-epilepsy drugs often fail to provide adequate protection against the severe seizures and neuropsychiatric comorbidities that occur in patients with SCN1A mutations. Furthermore, almost a third of all epilepsy patients do not achieve adequate seizure control, highlighting the urgent need to develop multimodal treatments that can effectively mitigate the broad spectrum of clinical features associated with refractory epilepsies, while minimizing unwanted side effects. In this exploratory R21 proposal, we will test the hypothesis that Huperzine A (Hup A), a naturally occurring sesquiterpene Lycopodium alkaloid, will be efficacious in the treatment of DS. This hypothesis is based on the biological properties of Hup A, its demonstrated clinical safety, tolerability, ability to improve cognitive function, and our preliminary data. We will use heterozygous Scn1a knockout mice (a model of DS) to evaluate the potential of Hup A to increase seizure thresholds and prevent spontaneous seizure generation (Aim 1) and to ameliorate cognitive and behavioral deficits (Aim 2). This clinically relevant proposal could lay the foundation for the development of a novel therapy to treat SCN1A-derived epilepsies. Furthermore, since SCN1A mutations lead to reduced neuronal inhibition, which is a shared mechanism underlying many common forms of epilepsy, the outcome of this study may have important, broad implications for the treatment of refractory epilepsies.